Thèse--Geneva. / At head of title: Université de Genève, Faculté de médecine. Institut de thérapeutique. Professeur Ed. Frommel. "Thèse no 2829." Includes bibliographical references.

Thèse--Geneva. / At head of title: Université de Genève, Faculté de médecine. Institut de thérapeutique. Professeur Ed. Frommel. "Thèse no 2829." Includes bibliographical references.

Prochlorperazine, a member of the piperazine subclass of phenothiazines, widely used as an anti-emetic, is susceptible to oxidation to sulfoxides. These are main metabolites and degradants of all phenothiazines which are found to be inactive at the dopamine receptors. Prochlorperazine causes photosensitivity effects in patients attributed to dechlorination at C2 with the release of HCI (Huang and Sands, 1967; Nejmeh and Pilpel, 1978; Moore and Tamat, 1980). The aim of this study is to investigate the thermal and photostability of prochlorperazine edisylate and mesylate salts in the solid state and in solution. Prochlorperazine is available as a fine chemical and in a variety of dosage forms, including injectables and tablets. According to ICH guidelines, any degradants greater than 0.1 % are required to be isolated and identified. In order to assess the photostability of the two salts, an HPLC method was developed and validated for linearity, accuracy and precision, selectivity, limit of detection, quantitation and ruggedness. Sulfoxides were synthesised for use as standards in the rate studies according to the well-known hydrogen peroxide method (Owens et al., 1989). The rate of prochlorperazine degradation in solution under various light sources (254 nm UV light, diffuse light and sunlight) was studied. The light sources used abovF were quantified using potassium ferrioxalate as a chemical actinometer). The photodegradation rate was found to be greater in ampoules sealed under nitrogen than air, but the thermal degradation was faster in ampoules sealed with air than those purged with nitrogen. Amber ampoules retarded the rate of degradation under all photolytic conditions. This is a vital consideration for the packaging and storage of prochlorperazine in injectables. Degradation was found to occur mainly by first-order kinetics and the degradation rate decreased in the following order: sunlight » UV light 254 nm > fluorescent I diffuse light. Solid state samples, however, were found to be relatively stable to the various light / heat conditions over a 6 month period when compared to prochlorperazine solutions, but still considerably unstable. Thus both storage and packaging is a vital consideration for prochlorperazine injectables. The thermal behaviour of mixtures of prochlorperazine with standard excipients, was assessed for potential interactions, using differential scanning calorimetry. For most of the excipients (magnesium stearate, stearic acid, Explotab®, AC-Di-Sol®, Encompress® and Ludipress®, lactose and Starch 1500®) disappearance or broadening of the melting endotherm of the drug indicated interactions. Lubritab®, however, was the only 'inert' excipient tested. Liquid chromatography - mass spectrometry (LC-MS) was used to determine the nature of the degradation products. The major degradation pathways included dechlorination and demethylation of the parent drug, as well as sulfoxidation and Noxidation. Prochlorperazine underwent dechlorination and sulfoxidation with subsequent photosubstitution to yield the 2-hydroxy derivative. The solid state photostudies showed the formation of dealkylated, oxidised and hydroxylated products, sulfoxides and dimers. Since N-demethylation, N-oxidation, sulfoxidation and aromatic hydroxylation are reported to occur in the in vitro metabolism of perazine derivatives, it does appear that there is some relationship between metabolites and photoproducts (Breyer, 1974). This study has been successful in providing understanding of the photolytic and thermal degradation pathways of prochlorperazine.

Four structurally related phenothiazines available in South Africa in a variety of dosage forms and as fine chemicals were investigated to ascertain whether their structural differences in terms of the 2-chloro-/ trifluoromethyl-substituents on the phenothiazine nucleus and the methyl-/ ß-hydroxethyl groups on the piperazine ring accouning for the differences in pharmacological activity can be correlated with their photostability².The four propyl piperazine-substituted derivatives are ranked in the following decreasing order of neuroleptic activity: fluphenazine> trifluoperazine> perphenazine > rochlorperazine. In order to assess their photostability an HPLC method was developed and validated for linearity, accuracy and precision, selectivity, limit of detection and quantitation and ruggedness. Preliminary solution photostudies under controlled light conditions (UV, sunlight, fluorescent light) indicated that the rate of degradation followed first-order kinetics with perphenazine the most susceptible to.photodegradation under all light conditions studied. In vitro and in vivo metabolism yielding the 5-sulphoxide and its reported presence on decomposition of the phenothiazines25 led to the development of a synthetic procedure suitable for the sutphoxides of all four derivatives based on the method proposed by Owens et al. in order to provide standards for comparison in the photostudies⁷. Since ICH regulations require that impurities> 0.1 % are examined and identified⁷⁴ and semi-preparative isolation of photoproducts proved unsuccessful, LC-MS having been well documented for structural.elucidation⁷⁵ ⁷⁵ ⁷⁶ ⁷⁷ was used to characterize solution (UV, sunlight, fluorescent light) and preliminary solid (UV) photostudies. The chloroderivatives underwent dechlorination and sulphoxidation with subsequent photosubstitution in the case of prochlorperazine to yield the 2-hydroxy derivative and sulphoxidation of the dechloro-derivative of perphenazine. The sulphoxides of both trifluoperazine and fluphenazine were formed with further oxidation to the respective sulphones occurring. Preliminary solid state (UV) photostudies showed fluphenazine to be the least stable with 30.71 % degradation as opposed to 7.57% for prochlorperazine, 4.28% for perphenazine and 7.10% for trifluoperazine witn sulphoxidation observed to be. the major degradation pathway. Since in vitro metabolism of perazine derivatives is reported to occur via N-oxidation, N-demethylation, sulphoxidation and aromatic hydroxylation¹⁸ it does appear that there is some correlation between metabolic and photoproducts. However the fact that solution (UV) photostudies indicates trifluoperazine to be the most and perphenazine the least stable does not concur with the proposed order of pharmacological activity.

No description available.

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Although the pharmacology and chemical effects of the phenothiazine derivatives have been extensively studied, very little is known concerning the biochemical mechanisms by which they exert their pharmacological effects. Underlying most of the work in this field is the belief that these compounds have certain enzymes as their primary targets or receptor sites. Thus chlorpromazine (CP Z) has been found to inhibit a wide variety of enzymes including cytochrome oxidase, glucose-phosphate dehydrogenase, hexokinase, and ATPase and to uncouple oxidative phosphorylation. However, excessive concentrations of CPZ were required to inhibit these systems and in most cases there was no good correlation between the antipsychotic behavior of these derivatives and their inhibitory capacity. Although the differences in inhibitory potency can not be explained yet in terms of binding sites, the approximate correlation between Ki and the usual daily dosage of these compounds in antipsychotic therapy, the failure of phenothiazines with little (if any) tranquilization properties to inhibit D-AAO, and the fact that the concentrations of drug required for inhibition (Ki) were well within the range which may be encountered in vivo all make more tenable the hypothesis that the phenothiazine tranquilizers might exert their effects by inhibiting flavo enzymes. [TRUNCATED] / 2031-01-01

Thesis (M.S.)--University of Wisconsin--Madison, 1963. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 45-54).

Thesis (Ph. D.)--University of Wisconsin, 1964. / Typescript. Vita. Abstracted in Dissertation abstracts, v. 25 (1964) no. 6, p. 3184. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

No description available.

Call number: LD2668 .T4 1955 M68 / Master of Science